The primary objective of this study is to evaluate the clinical efficacy of moderate-dose transcranial photobiomodulation (t-PBM) at different frequencies (10 Hz and 40 Hz) in patients with treatment-resistant depression (TRD). It further aims to explore the differential efficacy across various symptom subtypes, with a particular focus on the somatic symptom-dominant subtype. Additionally, this study will collect paired-pulse neurophysiological parameters (e.g., the ratio of cortical inhibition to excitation) to preliminarily explore the neural mechanisms underlying the modulation of cortical excitability by t-PBM intervention, and to analyze their correlation with the magnitude of clinical symptom improvement.

The specific aims of this study are as follows:

To evaluate the differential efficacy of t-PBM at varying frequencies (10 Hz vs. 40 Hz) in improving clinical depressive symptoms (as measured by scales such as HAM-D and MADRS).

To investigate the therapeutic response to t-PBM in patients with the somatic symptom-dominant depression subtype, analyzing its potential suitability for targeting specific symptoms.

To explore the changes in paired-pulse TMS parameters (e.g., SICI, ICF, and LICI) before and after t-PBM treatment, gaining preliminary insights into the potential association between its cortical modulatory effects and clinical outcomes.

This study aims to investigate the potential efficacy of transcranial photobiomodulation (tPBM) as an adjunctive antidepressant treatment in patients with treatment-resistant depression (TRD), with a specific focus on the subtype predominantly presenting with somatic symptoms. tPBM is a non-invasive neuromodulation technique that utilizes near-infrared light to stimulate the prefrontal cortex. It potentially improves energy metabolism and neural function while offering advantages such as high safety and minimal side effects. Although preliminary studies support its antidepressant potential, evidence regarding the relationship between treatment parameters, stimulation frequencies, and subtype-specific efficacy remains limited.

This prospective, randomized controlled trial expects to enroll 40 TRD subjects, who will be randomly assigned to either a 10 Hz or a 40 Hz group. Both groups will receive tPBM treatment twice a week for four consecutive weeks. Pre- and post-treatment clinical assessments will evaluate depressive symptoms (HDRS-17, MADRS), somatic symptoms (PHQ-15, DSSS), sleep quality, and overall functioning. Additionally, paired-pulse transcranial magnetic stimulation (TMS) will be utilized to record neurophysiological changes, specifically assessing alterations in cortical excitability and inhibition.

This study expects to clarify the differences in efficacy between distinct tPBM frequencies in TRD patients, particularly those with somatic symptom-dominant subtypes. Furthermore, it aims to establish a preliminary link among tPBM treatment parameters, neurophysiological markers, and clinical symptom changes, providing a scientific basis and empirical evidence for future precision neuromodulation therapies.

Inclusion Criteria:

Must have a current diagnosis of Major Depressive Disorder (MDD).

The clinical severity must be evaluated by a psychiatrist as moderate or above, defined as a Clinical Global Impression-Severity (CGI-S) score > 4 and a 17-item Hamilton Depression Rating Scale (HDRS-17) total score ≥ 18.

Must be currently receiving stable antidepressant treatment for at least four weeks but showing inadequate response (treatment-resistant). This study will be conducted as an add-on therapy.

Must have full behavioral capacity, normal intellectual functioning, and the ability to comprehend and sign the informed consent form.

Exclusion Criteria:

Individuals diagnosed with Bipolar Disorder or Schizophrenia.

Individuals with current or recent Substance Use Disorder.

History of organic brain lesions (e.g., neurodegenerative diseases, epilepsy, stroke) or any medical conditions affecting central nervous system function.

Individuals with abnormal intellectual functioning based on clinical judgment (e.g., suspected intellectual disability, severe learning difficulties).

Individuals who are currently pregnant (due to limited evidence regarding the safety of tPBM during pregnancy).

Any other condition that, in the investigator's judgment, would render the participant unable to cooperate, unsuitable for the study, or unwilling to sign the informed consent.

Participants and the clinical raters assessing the outcome measures (e.g., HDRS-17, MADRS) will be blinded to the assigned tPBM frequency. The device operator will not be blinded as they need to configure the stimulation parameters.